Nerve growth factor (NGF) acts through two membrane receptors. One is the relatively low affinity p75 receptor. The other is a 140 KDa high affinity receptor, known as TrkA.
NGF has potential use in the treatment of a wide range of disorders, such as various neurodegenerative disorders (including Alzheimer's disease), diabetes and leprosy.
However NGF can have various undesired agonist properties. These include an increase in pain sensitivity. The NGF-TrkA system provides a potential target for therapies for pain.
Various anti-TrkA antibodies have been produced. One such antibody is a monoclonal antibody which is referred to as 5C3 in WO 97/21732 (McGill University). However, this was found to be a TrkA agonist and is therefore not useful for reducing pain. Specifically, when binding to TrkA this antibody does not prevent the functional activation thereof.
An anti-TrkA monoclonal antibody known as MNAC13 is disclosed in WO 00/73344 (Societa Italiana Per La Ricerca Scientifica), from which EP-B-118138 (Lay Line Genomics SpA) is derived. This antibody and various derivatives thereof are said to be effective in preventing the functional activation of TrkA in a range of biological systems. The MNAC13 monoclonal antibody was used in a standard nociception test and was found to provide remarkable hypoalgesia.
A single chain Fv (ScFv) variant of this antibody is also disclosed in WO 00/73344 and is referred to therein as MNAC13 ScFv. This contains the variable light and heavy chain regions of the larger antibody linked together by a linker polypeptide, which joins the C-terminus of the VL region with the N-terminus of the VII region. This variant was found to bind TrkA as efficiently as MNAC13. The sequence of the light and heavy variable regions was compared with that of the corresponding regions of the antibody described in WO 97/21732 and it was found that there was only a low level of overall sequence identity therewith.
WO 06/131952 (Lay Line Genomics SpA) discloses medical uses of anti-TrkA antibodies in treating chronic pain. It provides evidence of this by using models of persistent pain, in particular the Chronic Constriction Injury (CCI) model.
WO 06/137106 (Lay Line Genomics SpA) discloses using an anti-TrkA antibody capable of inhibiting the binding between NGF and TrkA in combination with at least one opioid analgesic for treating or preventing pain. It is explained that this combination therapy allows a reduced opioid dosage to provide the same level of pain relief as a much higher dosage. This can therefore be useful in reducing the level of opioid side effects in pain therapy, because dosages can be lowered.
WO 05/061540 (Lay Line Genomics SpA & Scuolo Internazionale Superiore Di Studi Avanzati-Sissa) discloses a method of humanisation of antibodies in which structural data obtained from crystallographic studies are used to conduct the first design stages of humanisation. As examples, WO 05/061540 takes anti-TrkA antibodies, as disclosed in WO 00/73344, and anti-NGF antibodies as starting points, and then redesigns them using the disclosed method.
Whilst the humanised antibodies disclosed in WO 05/061540 are useful, there is a need to provide additional humanised antibodies so as to expand the possibilities for effective therapies.